基质金属蛋白酶-3启动子区-1612基因多态性与老年脑梗死发病及与炎性反应、氧化应激的相关性

Correlation of polymorphisms at the matrix metalloproteinase-3-1612 position of the promoter region with the inflammatory response and oxidative stress in elderly patients with cerebral ischemic stroke

目的观察老年脑卒中患者基质金属蛋白酶(MMP)-3启动子区-1612基因多态性和脑卒中发病风险及与炎性反应、氧化应激的相关性。方法回顾性分析2019年3月至2021年3月本院诊疗的老年脑卒中发病患者129例作为研究组,同时选择110例健康体检者作为对照组,检测MMP-3启动子区-1612基因多态性、炎性反应及氧化应激指标,并分析MMP-3基因多态性与各指标的相关性。结果与对照组相比,研究组的高血压、糖尿病、吸烟史比例明显增高(χ^(2)=16.05、17.19、14.19,均P<0.05),且空腹血糖及低密度脂蛋白胆固醇、同型半胱氨酸水平也增高(t=6.22,3.64,2.69,均P<0.05)。与MMP-3-5A/6A及6A/6A基因型患者相比,MMP-3基因5A/5A基因型患者血清炎症指标高迁徙率蛋白1(HM-BG1)、分形素趋化因子(FKN)、肿瘤坏死因子-α(TNF-α)、白细胞介素-1β(IL-1β)、白细胞介素-17(IL-17)含量增高(t=16.40、23.06、10.64、15.39、21.02;20.01、28.03、13.42、20.09、27.40,均P<0.05),同时血清氧化应激相关分子Kelch样ECH关联蛋白1(Keap1)、核因子E2相关因子(Nrf2)、抗氧化应答元件(ARE)、醌氧化还原酶1(NQO1)、血红素加氧酶-1(HO-1)表达也增加(均P<0.05),而上述指标在MMP-3-5A/6A和6A/6A基因型患者之间无明显差异(P>0.05)。5A/5A基因型和6A/6A基因型分别仅含970bp 1个条带和120bp 1个条带,而5A/6A基因型含97bp、120bp 2个条带;研究组中的5A/6A基因型数目与对照组差异无统计学意义(P>0.05),研究组中的5A/5A基因数目高于对照组[69(53.49%)比35(31.82%),χ^(2)=11.34,P<0.05]。MMP-3基因的多态性与脑卒中发生之间呈正相关(r=0.25,P<0.05)。MMP-3-1612基因多态性(OR=7.21,95%CI:1.13~1.83,P=0.01)及空腹血糖升高(OR=1.27,95%CI:1.18~2.06,P<0.001)、高同型半胱氨酸(OR=1.05,95%CI:1.07~1.58,P<0.01)、高血压(OR=5.41,95%CI:1.14~4.46,P<0.01)、低密度脂蛋白胆固醇升高(OR=4.03,95%CI:1.03~2.35,P=0.02)、冠心病(OR=1.17,95%CI:1.47~3.19,P<0.01)以及糖尿病(OR=8.52,95%CI:1.32~4.71,P<0.01)等均可增加脑卒中发生风险。结论老年脑卒中患者MMP-3启动子区-1612基因多态性和发病风险、炎性反应和氧化应激密切相关,MMP-3基因多态性是脑卒中发生的危险因素之一。

Objective To investigate the association of polymorphisms at the matrix metalloproteinase(MMP)-3-1612 position of the promotor region with the inflammatory response and oxidative stress in elderly patients with cerebral ischemic stroke.Methods In this retrospective study,129 elderly patients with cerebral infarction diagnosed and treated in our hospital between March 2019 and March 2021 were enrolled as the study group,and 110 healthy subjects were selected as the control group.Polymorphisms of the MMP-3-1612 position in the promotor region,the inflammatory response and oxidative stress were examined using appropriate parameters and the associations between them were analyzed.Results Compared with the control group,the proportions of patients with hypertension,diabetes,and smoking history in the study group were significantly higher(χ^(2)=16.05,17.19,14.19,all P<0.05),and the levels of fasting blood glucose,low-density lipoprotein,and homocysteine were also significantly higher(t=6.22,3.64,2.69,all P<0.05).Meanwhile,compared with patients carrying the MMP-3-5A/6A or the MMP-3-6A/6A genotype,the levels of serum inflammatory markers such as high mobility group box-1 protein(HMGB1),fractalkine(FKN),tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β)and interleukin-17(IL-17)in patients carrying the MMP-3 gene 5A/5A genotype were significantly higher(all P<0.05).In addition,the expression of serum oxidative stress-related molecules Kelch-like ECH-associated protein 1(Keap1),nuclear factor erythroid-2 related factor2(Nrf2),antioxidant response element(ARE),quinone oxidoreductase 1(NQO1),and heme oxygenase-1(HO-1)was also significantly increased(all P<0.05),but there was no difference in these markers between patients carrying the MMP-3-5A/6A genotype and patients carrying the MMP-3-6A/6A genotype(P>0.05).Patients carrying the 5A/5A genotype and the 6A/6A genotype exhibited only one 97 bp band and one 120 bp band,respectively,while the patients carrying the 5A/6A genotype exhibited two 97 bp bands and two 120 bp bands.There was no statistical difference in the number of patients carrying the 5A/6A genotype in the cerebral infarction group compared with the control group(P>0.05),and the number of patients carrying the 5A/5A genotype in the cerebral infarction group was higher than that in the control group(69%or 53.49%vs.35%or 31.82%,χ^(2)=11.34,P<0.05).Polymorphisms of the MMP-3 gene had a positive correlation with the risk of stroke(r=0.25,P<0.05).MMP-3-1612 gene polymorphism(OR=7.21,95%CI:1.13-1.83,P=0.01),elevated blood glucose(OR=1.27,95%CI:1.18-2.06,P<0.001),high homocysteine(OR=1.05,95%CI:1.08-1.58,P<0.01),hypertension(OR=5.414,95%CI:1.140-4.46,P<0.01),elevated low-density lipoprotein(OR=4.03,95%CI:1.03-2.35,P=0.02),coronary heart disease(OR=1.17,95%CI:1.47-3.19,P<0.01)and diabetes(OR=8.52,95%CI:1.32-4.71,P<0.01)were risk factors for cerebral infarction.Conclusions In elderly patients with cerebral infarction,polymorphisms of the MMP-3-1612 position in the promotor region is closely related to the risk of cerebral ischemic stroke,the inflammatory response and oxidative stress.MMP-3 gene polymorphisms are risk factors for stroke.